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Biomedical subjects

J W Olson

Publications and source records attributed to J W Olson.

At least 73 records · Page 4Linked to original sources
PubMed1988

Brain ornithine decarboxylase activity following transient cerebral ischaemia: relationship to cerebral oedema development.

Ornithine decarboxylase (ODC) activity, the first and generally rate-limiting enzyme for polyamine synthesis, is stimulated in permanent focal cerebral ischaemia in areas of incomplete ischaemia which are developing ischaemic brain oedema. As polyamines are ubiquitous ornithine-derived molecules which are obligatory in cold-induced vasogenic oedema, we studied the effect of transient dense cerebral ischaemia with reperfusion on ischaemic oedema development and ODC activity. Fifty-nine Mongolian gerbils were anaesthetized with ketamine hydrochloride (160 mg/kg i.p. plus supplementation as needed). Both common carotid arteries were isolated and a tracheotomy placed in position. EEG was monitored with needle electrodes and temperature maintained at 37-38 degrees C. Twenty-nine gerbils underwent 40 min of bilateral carotid artery occlusion followed by reperfusion times of 10 min, 1, 2, 4, 6 or 8 h. Non-ischaemic control groups were monitored for equal intervals. At sacrifice, the brain was rapidly removed and forebrain samples analysed for ODC activity (enzymatic assay) and cerebral oedema (gravimetric determination). Marked loss of EEG amplitude was noted in all gerbils subjected to bilateral carotid artery occlusion. Ischaemia produced significant levels of cortical oedema throughout the reperfusion period (maximal decrease in specific gravity at 4 h postischaemia; control: 1.0456 +/- 0.0013; ischaemia: 1.0355 +/- 0.0021, mean +/- SD; p less than 0.0001). Significant subcortical oedema was produced at 10 min, 2 and 4 h postischaemia. A biphasic response was observed in brain ODC activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Polyamine content in pulmonary arteries from rats with monocrotaline-induced pulmonary hypertension.

Based on the documented role of polyamines in regulation of cell growth and differentiation, we have proposed that these organic cations are essential for hypertrophic and hyperplastic responses of pulmonary vascular cells which underlie development of hypertensive pulmonary vascular disease. In support of this contention, we have shown in rat models of monocrotaline (MCT)- and chronic hypoxia-induced pulmonary hypertension that whole-lung polyamine contents are elevated and that blockade of polyamine synthesis forestalls development of hypertensive pulmonary vascular remodeling and sustained pulmonary hypertension. To determine if the involvement of polyamines in pulmonary hypertension could be ascribed to events occurring in cells of the vascular wall, as opposed to parenchymal or airways cells, the present study measured polyamine contents as a function of time in macroscopic pulmonary arteries from MCT-treated rats. Rats were given MCT or its vehicle and, at 1,4,7, and 21 days post-treatment, the contents of putrescine, spermidine, and spermine were assessed in whole right lung and in an arterial segment from the left lung consisting of the first and extending to the sixth intrapulmonary branch. Relative to control animals, contents of putrescine and spermidine were elevated in whole lung at 4, 7 and 21 days post MCT while the content of spermine was elevated above control at 21 days. In pulmonary arterial segments, contents of putrescine and spermidine were augmented significantly at 7 and 21 days after MCT treatment. Spermine content in arterial segments was increased at 21 days. Right ventricular hypertrophy indicative of sustained pulmonary hypertension was not evident until 21 days post-treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Evidence that hypoxic pulmonary vascular remodeling in rats is polyamine dependent.

This study tested the hypothesis that the polyamines, a family of low-molecular-weight organic cations with documented regulatory roles in cell growth and differentiation, are mediators of chronic hypoxia-induced pulmonary vascular remodeling. Relative to room air controls, chronically hypoxic animals (inspired O2 fraction = 0.1; 21 days) exhibited higher pulmonary arterial pressures (measured in room air), thicker medial layers in pulmonary arteries of 50-100 microns diam, increased hematocrits, and right ventricular hypertrophy. In addition, lung contents of the polyamines, putrescine, spermidine, and spermine were greater in hypoxic animals than in controls. alpha-Difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, attenuated the hypoxia-induced elevations in lung putrescine and spermidine content and blunted the increases in pulmonary arterial pressure and medial thickness. Neither the increased hematocrit nor right ventricular hypertrophy associated with chronic hypoxia were abrogated by DFMO. In addition, DFMO failed to influence vasoconstrictor responses provoked by acute hypoxic ventilation in isolated, buffer-perfused rat lungs. These observations suggest that depression of polyamine biosynthesis with DFMO blunts the sustained increase in pulmonary arterial pressure by attenuating hypoxia-induced medial thickening.

Amines↗
PubMed1986

Vascular hyperresponsiveness in perfused lungs from monocrotaline-treated rats.

Studies were conducted in isolated, buffer-perfused lungs to determine whether altered pulmonary vascular responsiveness could contribute to the evolution of monocrotaline (MCT)-induced pulmonary hypertension. Adult male rats were given a single subcutaneous injection of either 105 mg/kg MCT or its vehicle and vascular responsiveness to angiotensin II, ventilatory hypoxia (3% O2), and KCl was assessed in isolated, buffer-perfused lungs at 4, 7, and 14 days post-treatment. Relative to preparations derived from control animals, vasopressor responses induced by 0.1 microgram, but not 0.05 microgram angiotensin, were augmented at 4 and 7 days but not at 14 days post MCT. Pulmonary vasoconstriction evoked by hypoxic ventilation was enhanced at 4 days but not at 7 or 14 days posttreatment. Pressor responses induced by 30 and 45 mg KCl were not different in treated animals relative to controls at any time post-MCT administration. MCT provoked perivascular edema, but this factor did not seem to contribute to vascular hyperresponsiveness, since the time course of edema did not parallel the time course of augmented responsiveness. Results of the present study indicate that MCT, by an unknown mechanism, causes an early and transient increase in pulmonary vascular responsiveness to some but not all vasoconstrictors. Because the enhanced responsiveness occurred prior to development of pulmonary hypertension, it is unlikely that this alteration contributes to the sustained elevation in pulmonary arterial pressure.

Angiotensin II↗
PubMed1986

Altered pulmonary vascular smooth muscle responsiveness in monocrotaline-induced pulmonary hypertension.

Studies were conducted to determine whether experimental pulmonary hypertension is associated with alterations in pulmonary vascular smooth muscle responsiveness. Adult male rats were given a single s.c. injection of monocrotaline (105 mg/kg) or saline and were sacrificed 4, 7 or 14 days later. Segments of the main trunk and right extrapulmonary artery and an intrapulmonary artery were isolated for determination of vascular reactivity to contractile and relaxant agonists. Monocrotaline treatment caused changes in mechanical properties of pulmonary arteries in that vessels isolated from rats 14 days after monocrotaline administration required greater passive loads to achieve maximal active force development. Cumulative concentration-response curves were generated to potassium chloride, angiotensin II, norepinephrine, isoproterenol and acetylcholine. Vascular contractility was enhanced in main pulmonary artery 4 days after monocrotaline injection but no differences in responsiveness between control and monocrotaline exposed vessels were observed 7 days post-treatment. In contrast, significant decreases in contractility with a specific loss in the response to angiotensin II were observed in pulmonary arteries isolated from rats 14 days after monocrotaline administration. These vessels also were less responsive to the relaxant effects of isoproterenol and acetylcholine when compared to control vessels. These results demonstrate that changes in pulmonary vascular smooth muscle responsiveness occur during evolution of pulmonary hypertension induced by monocrotaline. Enhanced contractility may contribute to inappropriate vasoconstriction early in the development of hypertensive pulmonary vascular disease but does not appear to be involved in sustained elevations in pulmonary artery pressure. Diminished relaxation observed after pulmonary hypertension was well established may contribute to the loss in efficacy of vasodilators in the long-term management of pulmonary hypertension.

Acetylcholine↗
PubMed1985

Chronic cigarette sidestream smoke exposure increases rat trachea ornithine decarboxylase activity.

The effect of chronic cigarette smoke exposure on the activity of rat trachea and lung ornithine decarboxylase (ODC) and s-adenosyl-methionine decarboxylase (AdoMet-DC) was determined. Male rats were exposed once daily for 10 min to mainstream (MS) or different sidestream (SS) dilutions of fresh Kentucky 2R1 cigarette smoke or air (sham) for 4, 8 or 20 weeks. Eight weeks of MS smoke significantly increased lung and trachea ODC activity. All dilutions of SS smoke exposure caused significant increases in trachea ODC activity, but SS smoke did not influence lung ODC activity. The data demonstrate that long term exposure to passive smoke generated from cigarettes can increase rat trachea ODC activity.

Adenosylmethionine Decarboxylase↗
PubMed1985

Enhanced phosphatidylinositol kinase activity is associated with early stages of hepatocarcinogenesis and hepatocellular carcinoma.

Liver phosphatidylinositol (PI) kinase activity was determined in rats exposed to two different hepatocarcinogenic regimens. In contrast to partial treatment regimens the complete Solt and Farber hepatocarcinogenic regimen caused a significant increase in liver PI kinase activity at day 11 after partial hepatectomy. PI kinase activity in hepatocarcinomas removed 15 1/2 months after initiation of the complete Solt and Farber regimen was 2-fold higher than normal liver tissue surrounding the tumors. Compared to a choline supplemented diet a hepatocarcinogenic regimen consisting of a diet deficient in choline and methionine significantly increased liver PI kinase activity after 26 days. These data demonstrate that liver PI kinase activity is selectively elevated during hepatocarcinogenesis.

1-Phosphatidylinositol 4-Kinase↗
PubMed1985

Liver tyrosine kinase activation during early stages of chemical hepatocarcinogenesis.

Protein phosphorylation at tyrosine residues is believed to be involved in several important cellular processes because tyrosine-specific protein kinase activation is associated with stimulation of cellular proliferation by hormones and growth factors, embryogenesis, and retroviral cell transformation. Because cell proliferation is thought to be an essential component of chemical carcinogenesis, liver tyrosine-specific protein kinase activity was examined during the early stages of the Solt and Farber chemical hepatocarcinogenesis model. Rats were given diethylnitrosamine in one dose (200 mg/kg, IP) followed by 2 weeks of dietary 0.02% 2-acetylamino-fluorene starting at day 14 after diethylnitrosamine, followed by partial hepatectomy on day 21. By day 32 this regimen produces a relatively synchronized population of hyperplastic liver nodules up to 1.5 mm in diameter. Rats were sacrificed on day 32, their livers were perfused with cold normal saline, homogenized, and centrifuged at 1,000g for 10 min. The resulting supernatant was centrifuged at 30,000g for 30 min and the pellet was assayed for tyrosine kinase activity using the synthetic peptide [Val5]angiotensin II as substrate. Rats that received the complete regimen had a 2.6-fold increase in their liver tyrosine kinase activity as compared to sham controls (2.4 pmoles/min/mg protein vs 6.4 pmoles/min/mg protein, P less than .05). In contrast, rats that received a partial regimen (ie, partial hepatectomy, or 2-acetylaminofluorene + partial hepatectomy, or diethylnitrosamine + 2-acetylaminofluorene) did not have elevated tyrosine kinase activity nor did they have hyperplastic nodules. These preliminary data suggest that activation of liver tyrosine kinase is associated with the very early stages of chemical hepatocarcinogenesis.

Animals↗
PubMed1985

High-performance liquid chromatographic analysis of pulmonary metabolites of Leu- and Met-enkephalins in isolated perfused rat lung.

A high-performance liquid radiochromatographic analytical system has been developed which allows the determination of [3H]Leuenkephalin, [3H]Met-enkephalin and their potential metabolites [3H]TyrGlyGlyPhe, [3H]TyrGlyGly, [3H]TyrGly and [3H]tyrosine. Using this procedure, the biotransformation of each of the above enkephalins after 20 min of recirculating transit through isolated perfused rat lungs resulted in the formation of two major metabolites: tyrosine and TyrGlyGly in each case. The results indicate that significant metabolism of enkephalins may occur in the pulmonary circulation.

Animals↗
PubMed1985

Suppression of polyamine biosynthesis prevents monocrotaline-induced pulmonary edema and arterial medial thickening.

Previous work in our laboratory has shown that the continuous administration of alpha-difluoromethylornithine (DFMO), a highly specific irreversible inhibitor of ornithine decarboxylase (ODC), which is the rate-limiting enzyme in polyamine biosynthesis, prevented the development of pulmonary hypertension and right ventricular hypertrophy induced in rats 21 days after a single injection of monocrotaline (MCT). We now report that DFMO treatment did not influence the proposed first step of MCT pneumotoxicity, that is, the hepatic metabolism of MCT to toxic pyrrolic metabolites. In contrast, DFMO treatment blunted the development of lung perivascular edema at Day 7, inhibited the respective four- and twofold increases in lung putrescine and spermidine contents at Day 21 without significantly altering spermine content, and prevented the arterial medial thickening at Day 21. It thus appears that increased lung polyamine biosynthesis may be essential for the expression of MCT-induced perivascular edema as well as the development of the medial thickening stage of MCT-induced hypertensive pulmonary vascular disease.

Animals↗
PubMed1985

Effect of nicotine and N'-nitrosonornicotine on rat lung and trachea ornithine decarboxylase activity.

The exposure of rats to tobacco smoke was previously reported to cause an increase in lung and trachea ornithine decarboxylase (ODC) activity. In the present paper we test the effects of the tobacco-specific components nicotine and N'-nitrosonornicotine (NNN) on lung and trachea ODC activity. In addition, a procedure for the synthesis of analytically pure NNN is described. NNN caused an increase in lung ODC activity 6 h and also 4 days after a single s.c. dose. NNN did not alter trachea ODC activity. A single s.c. dose of nicotine activated both lung and trachea ODC in a dose-response fashion. It is possible that the impact of these tobacco-specific agents upon respiratory tract polyamine biosynthesis could contribute to some of the multi-faceted effects associated with cigarette smoking.

Animals↗
PubMed1985

Polyamine and prostaglandin markers in focal cerebral ischemia.

This study examines the pathophysiology of stroke secondary to focal cerebral ischemia. The interaction of arachidonic acid metabolites and polyamines, a class of ubiquitous ornithine-derived molecules with important membrane effects on edema, Ca++-dependent endocytosis, platelet function, and prostaglandin (PG) formation, are correlated with regional changes in H2 clearance, cerebral blood flow (rCBF), ischemic edema, and somatosensory evoked responses (SSERs) after middle cerebral artery (MCA) occlusion. Thirty cats were studied up to 3 hours before and 6 hours after right MCA occlusion. Four areas of brain showing different levels of perfusion after MCA occlusion were sampled for tissue levels of PGs: 6-keto-PGF1 alpha, PGE2, and as well as thromboxane B2 (TXB2), ornithine decarboxylase activity (ODC) (a measure of polyamine activity) and gravimetric determination of cerebral edema. After right MCA occlusion, right hemisphere SSER amplitude decreased and interpeak latency increased markedly. rCBF was distributed into zones of dense, partial, and no ischemia ranging from 12.6 to 59.4 ml/100 g/minute. Ischemic edema was distributed inversely to rCBF and was increased in areas of dense ischemia (85.2 +/- 0.5%) and ischemia (82.7 +/- 0.7%), but not in partially ischemic or control areas. 6-Keto-PGF1 alpha (1257.3 pg/mg), PGE2 (1628.5 pg/mg), and TXB2 (1572.8 pg/mg) were all significantly (P less than 0.05) increased in areas of partial ischemia that had not yet developed edema. ODC levels were significantly elevated (3812 pmole/g/hour, P less than 0.05) and increased with time in areas of slightly denser ischemia that showed an intermediate increase in edema, but not the presence of infarction. This is the first demonstration that ODC, the rate-limiting enzyme for polyamine synthesis, is stimulated by cerebral ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Pulmonary mechanical, ventilatory, and gas exchange abnormalities in rats with monocrotaline-induced pulmonary hypertension.

Recent clinical studies have suggested that peripheral airways dysfunction contributes to the pathogenesis of idiopathic pulmonary hypertension. To determine whether similar peripheral airways defects occur in a common animal model of pulmonary hypertension, pulmonary function tests were performed in adult male rats rendered pulmonary hypertensive with a single subcutaneous injection of monocrotaline. At 20 days post treatment, animals exhibited well-developed right ventricular hypertrophy coincident with significant changes in lung volumes, pulmonary mechanics, and gas exchange function indicative of a severe combined restrictive and obstructive airways disorder. Morphologic changes in alveolar integrity compatible with such a pulmonary defect also were observed in monocrotaline-treated animals. The specific changes in pulmonary function observed in monocrotaline-treated rats were qualitatively similar to abnormalities reported in patients with idiopathic pulmonary hypertension. These results demonstrate that significant pulmonary mechanical, ventilatory, and gas exchange dysfunction is present in rats with monocrotaline-induced pulmonary hypertension and highlight the suitability of this model for investigating a potential contributory role of pulmonary function abnormalities in the pathogenesis of this disorder.

Animals↗
PubMed1985

Pulmonary metabolism of exogenous enkephalins in isolated perfused rat lungs.

Metabolism of enkephalins during transit through the pulmonary circulation may be of significance in regulating systemic levels of these opioids. To determine whether Leu- and Met-enkephalin are metabolized by the pulmonary circulation, [3H]Tyr-Leu-enkephalin (10 microM) or [3H]Tyr-Met-enkephalin (10 microM) were each administered to isolated rat lungs perfused in a recirculating manner with a physiologic salt solution and a recently developed high-performance liquid radiochromatographic analytical method was used to identify and quantitate metabolites in the perfusion medium. Both Leu- and Met-enkephalin were metabolized in a curvilinear, time-dependent manner. The principal metabolites were identified as tyrosine and Tyr-Gly-Gly. Neither Tyr-Gly nor Tyr-Gly-Gly-Phe were detected in significant amounts. After a 20-min perfusion, residual Leu- or Met-enkephalin accounted for 28.4 and 21.5%, respectively, of the radioactivity present in the perfusate. In addition, 97% of the initial radioactivity for both Leu- and Met-enkephalin were found in the perfusion medium, indicating that neither the parent compounds nor metabolites were avidly sequestered in pulmonary tissue. The angiotensin converting enzyme inhibitor, captopril (18 microM) blocked the formation of Tyr-Gly-Gly and attenuated slightly the production of tyrosine. Inhibition of aminopeptidase with bestatin (116 microM) blocked the formation of tyrosine and enhanced production of Tyr-Gly-Gly. Inhibition of enkephalinase with thiorphan (0.3 microM) did not appear to affect Met-enkephalin metabolism. These observations indicate that in isolated, buffer perfused rat lungs Leu- and Met-enkephalin are metabolized during pulmonary transit by at least two enzymes, angiotensin converting enzyme and aminopeptidase.

Aminopeptidases↗